The long-term goal of this research program is to elucidate molecular mechanisms of obesity and obesity- associated metabolic diseases. Obesity is a major risk factor for hypertension, atherosclerosis, stroke, heart attack, type 2 diabetes and cancer, which reduces both lifespan and life quality. Healthcare costs for obesity and obesity-associated diseases are huge and continue to rise rapidly. Recent identification of the adipose hormone leptin has transformed our understanding of the regulation of body weight and energy homeostasis. Leptin, which is produced by adipose tissue and secreted into the bloodstream in proportion to the total fat mass, binds to and activates its receptor in the hypothalamus, relaying peripheral nutritional signals to the central nervous system. Impaired leptin responses (leptin resistance) lead to overweight and obesity. Leptin resistance is mainly caused by the inhibition of cell signaling downstream of the leptin receptor (LEPRb). LEPRb binds to and activates JAK2, a cytoplasmic tyrosine kinase that mediates key signaling pathways in response to leptin. We recently identified SH2-B, an SH2 and PH domain-containing adaptor protein, as a JAK2-interacting protein in cells. We hypothesize that SH2-B is a key enhancer of leptin regulation of body weight and energy homeostasis, and defects in SH2-B expression and action may be an important risk factor for leptin resistance and obesity. To test this hypothesis, we disrupted the SH2-B gene in mice. We demonstrate that SH2-B knockout mice are severely leptin resistant and obese. In this proposal, we shall extend our preliminary work and firmly establish the essential role of SH2-B in the control of body weight and energy homeostasis. We shall elucidate the molecular mechanisms of SH2-B action using biochemical, genetic and physiological approaches. The findings from this project will provide a scientific basis for design of new therapeutic treatments for obesity and obesity-associated metabolic diseases by targeting SH2-B expression and action. Specific Aims are: 1. Determine whether SH2-B regulates energy metabolism and body weight by directly enhancing leptin sensitivity in hypothalamic LEPRb-neurons. 2. Determine whether SH2-B regulates energy metabolism and body weight by directly modulating the activity of hypothalamic AgRP-neurons. 3. Determine whether SH2-B differentially regulates leptin sensitivity in the LEPRb-neurons governing energy intake versus energy expenditure.